Project Summary/Abstract The long-term objective of this project is to characterize how attention and acetylcholine affect visual perception and the brain's representation of the visual environment. Acetylcholine is a naturally occurring neurotransmitter, and acetylcholine release is elevated during periods of sustained attention. Both acetylcholine and attention enhance aspects of visual perception, but the underlying brain mechanisms are poorly understood. The proposed work will address these questions in healthy human subjects by using functional magnetic resonance imaging (fMRI) to measure the brain's responses to visual stimuli, Our previous studies have shown that increasing levels of acetylcholine in the brain enhances the spatial resolution of the brain's representation of the visual environment. The proposed research will document exactly which brain areas mediate this effect of acetylcholine and will also characterize the effects of attention on these measures of spatial resolution in the brain. The consequences of enhanced spatial resolution for visual perception will also be investigated. This work may have particular significance for the treatment of macular degeneration, a disease characterized by loss of central vision. Patients suffering from macular degeneration must rely exclusively on peripheral vision, and the low spatial resolution of peripheral vision severely impairs their ability to read and to recognize faces and other visual objects. We will also examine the effects of acetylcholine and attention on the reliability of the brain's representations of the visual environment. Our preliminary studies show that increasing acetylcholine levels reduces the variability of the brain's response to repeated presentations of a visual stimulus. In other work, we have shown that increasing acetylcholine dramatically boosts perceptual learning (the improvement in visual ability following practice of particular tasks). The enhanced stability of brain representations following increases in acetylcholine may be responsible for the improvement in perceptual learning. In addition, we have found that acetylcholine can facilitate the beneficial effects of attention on perception. The proposed research will directly examine the relationships among attention, acetylcholine, brain activity, and visual perception. Drugs that enhance the effects of acetylcholine (cholinesterase inhibitors) are used to treat cognitive deficits in Alzheimer's disease. Although the biochemical actions of these drugs are well characterized, their perceptual and cognitive effects and the neural correlates of these effects are less well understood. We will use the cholinesterase inhibitor donepezil (trade name: Aricept) to manipulate brain acetylcholine levels in order to shed light on the role of acetylcholine in attention and perception and to better understand the mechanisms by which these drugs improve cognitive function. In addition, a better understanding of the neural substrates of attention is important for the development of more effective treatments of diseases that affect attention, including attention deficit disorder, schizophrenia, and Alzheimer's disease.